As is well known, 1-androstene derivative is a compound having a double bond between the first and the second carbons of an androstane, and representative drugs having such chemical structure include finasteride and dutasteride.
Finasteride (17β-(N-tert-butylcarbamoyl)-5α-4-aza-androst-1-en-3-one), the compound of formula (II) having an androstene backbone, is known to be effective in treating benign prostatic hyperplasia and androgenic alopecia:

Benign prostatic hyperplasia and androgenic alopecia are caused by binding of excessive 5α-dihydrotestosterone (DHT) derived from testosterone to an androgen receptor. The conversion of testosterone into DHT is accomplished by testosterone 5α-reductase, which can be inhibited by finasteride. Such inhibition of testosterone 5α-reductase by finasteride results in a decreased DHT concentration in plasma and cells, and thus rapid recovery of prostate and increased hair growth. In addition to its effectiveness to benign prostatic hyperplasia and androgenic alopecia, finasteride has excellent drug tolerance and exhibits light, temporary side effects. Currently, finasteride is the only orally administrable product among the two hair-growth agents approved by the United States Food and Drug Administration.
A process for preparing finasteride is disclosed in U.S. Pat. No. 4,760,071 and Korean Patent Publication No. 1990-0001206. As show in Scheme 1, the carboxylic group at the 17β-position of 3-oxo-4-aza-5α-androstane-17β-carboxylic acid of formula (III) is converted into a pyridylthioester group of formula (IV) using 2,2′-pyridyldisulfide. Next, the compound of formula (IV) is reacted with tert-butylamine to obtain 17β-tert-butylcarbamoyl compound of formula (V), followed by introducing a double bond between the first and the second carbon atoms using bezeneselenic anhydride to obtain finasteride of formula (II).

The above process is advantageous in that the dehydrogenation reaction can be accomplished in one step. However, it suffers from a high production cost due to the usage of expensive reagents such as 2,2′-pyridyldisulfide and bezeneselenic anhydride, and a poor purity, e.g., in the range of 75 to 80%, due to the production of undesired by-products. Further, it is difficult to improve the purity of the obtained finasteride even if it undergoes such purification steps as column chromatography and recrystallization.
European Patent No. 298,652, U.S. Pat. Nos. 5,084,574 and 5,116,983, and Korean Patent Publication No. 1996-0015038 disclose a process for preparing finasteride, which comprises silylating the 3-oxo group in the above compound of formula (III) using bistrimethylsilyltrifluoroacetamide (BSTFA), followed by introducing a double bond between the first and the second carbon atoms using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidizing agent.
However, this process, in addition to the usage of expensive reagents, has extra problems in that the reaction should be carried out under a nitrogen gas flow and with an anhydrous solvent due to BSTFA's sensitivity to water, and excessive impurities may be produced due to the use of a quinone as an oxidizing agent under reflux condition for 20 hours in a solvent having a high boiling point, i.e., 1,4-dioxane. Further, substantial losses of the obtained product may occur during a purification step, and, therefore, it is not suitable for mass production.
U.S. Pat. No. 5,091,534 and European Patent Nos. 428,366 and 473,225 teach a process for preparing finasteride, which comprises silylating the compound of the above formula (III) in the presence of a base and introducing a halogen such as iodine and bromine into the 2-position of the compound, followed by introducing a double bond between the first and the second carbon atoms using a strong base such as potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
However, this process also suffers from a poor purity (about 80%) since the reactants and products tend to be decomposed due to the high pH of the reaction solution containing the strong base, and a low yield after several purification steps (about 30%).
A method for dehydrogenating a 3-oxo-4-azasteroid compound through a sulfinate intermediate is disclosed in J. Med. Chem. 27(12): 1690 (1984). First, as shown in Scheme 2, the compound of formula (VI) is reacted with dimethylsulfate to obtain the compound of formula (VII) having a protected amide. Next, the compound of formula (VII) is reacted with diphenyldisulfide in the presence of a strong base such as lithium diisopropylamide (LDA) at −78° C. to produce the compound of formula (VIII) having a phenylsulfide group at the 2-position, and then the amide of the compound of formula (VIII) is deprotected in the presence of a strong acid to obtain the compound of formula (IX). Finally, the compound of formula (X) is prepared by using an oxidizing agent and the compound of formula (XI) is obtained by refluxing the compound of formula (X) in toluene.

However, this method employs the unnecessary steps of protecting and deprotecfing the amide group, consists of five complicated steps, and uses an inflammable diisopropylamide. Further, it is performed at extremely low temperature, i.e., −78° C., which is not practically applicable to an industrial scale.
As discussed above, the conventional methods for preparing finasteride are disadvantageous in that they employ water-sensitive, expensive or toxic reagents, require extreme reaction conditions or comprise complicated multiple steps, thereby rendering them unsuitable for mass production. Especially, in most conventional methods, finasteride is prepared under a vigorous condition or in the presence of a strong base in a final step, resulting in excessive impurities.
There are strict provisions as to the impurities of finasteride. For example, according to the provision of European Pharmacopeia, the amount of individual impurity A, B and C identified below, may not exceed 0.3% and the total amount of the impurities should not exceed 0.6%. Similarly, according to U.S. Pharmacopeia, the amount of individual impurity A, B and C should not exceed 0.5% and the total amount thereof should not exceed 1.0%.
Impurity A has a structure that the double bond of finasteride is saturated, impurity B has a methylester group at the 17β position, instead of the tert-butylamino group of finasteride, and impurity C contains an extra double bond between the fifth and the sixth carbon atoms.

Further, finasteride cannot be easily purified using a conventional method such as recrystallization when it is mixed with an excessive amount of the above impurities A to C, since finasteride and impurities A to C have similar structures. In particular, during the recrystallization of finasteride to meet the amount of impurity A below 0.3%, loss of yield is inevitably caused, thus it renders the final yield of finasteride only 30 to 40%. Further, impurities A and C cannot be easily removed even using column chromatography. Accordingly, there has been a need to develop a method for preparing highly pure 1-androstene derivatives including finasteride.